The stress-activated protein kinases (SAPKs), also referred to as c-jun-NH2-terminal kinases (JNKs), comprise a subfamily of proteins which belongs to the mitogen-activated protein kinase (MAPK) group of protein kinases. The MAPK pathways have been implicated as a mechanism by which signals are transduced from the cell surface to the nucleus in response to a variety of different stimuli and participate in intracellular processes by further inducing the phosphorylation of intracellular substrates such as other protein kinases and transcription factors.
The SAPK family includes, in part, p54 SAPKα/β/JNK2 and p45 SAPKγ/JNK1 and the p38 MAPKs (α,β, βII, γ, and δ). Guan, et al., J. Biol. Chem., 1998, 273, 28670-28676. JNK is described in U.S. Pat. Nos. 5,534,426, 5,593,884 and 5,605,808, and WO 95/03324. It has been reported previously that the inflammatory cytokine interleukin-1β (IL-1β) rapidly activates the JNK/SAPKs and p38 MAPKs and also induces cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. Guan et al., J. Biol. Chem., 1997, 272, 8083-8089. Interestingly, it has been suggested that the MAPK pathway is also involved in regulating prostaglandin biosynthesis. Lin et al., Cell, 1993, 72, 269-278; Kramer et al., J. Biol. Chem., 1996, 271, 27723-27729. The requirement of JNK/SAPK activity for cytokine-induced prostaglandin biosynthesis, has also been reported. Xie et al., J. Biol. Chem., 1995, 270, 27622-27628; Xie et al., Mol. Cell. Biol., 1994, 14, 6531-6539.
The elucidation of all the aforementioned pathways, however, still remains unclear. Also, the sequence of events through which a signal induced by a noxious stimulus (UV irradiation, heat shock, X-ray, etc.) gets transmitted into the nucleus, and thus renders certain nuclear factors to act as oncogenes, or transcribe and activate other subsequent pathways, is vaguely understood. Recent work has implicated the JNK/SAPK pathway in connection with the induction of transcription factors as a response to stress signals, thereby demonstrating the importance of SAPKs in the activation of ATF3, a member of the ATF/CREB family of transcription factors. Hai, et al., Gene Expression, 1999, 7, 321-335. The JNK/SAPK pathway has been also implicated in cell proliferation and stress-induced programmed cell death (apoptosis). Kyriakis, et al., BioEssays, 1996, 18 567-577; Xia, et al., Science, 1995, 270, 1326-1331; Brenner, et al., J. Biol. Chem., 1997, 272, 22173-22181.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids have been the most widely used pain killers for many years. In some circumstances, NSAIDs are able to provide better analgesia than opioids. The NSAIDs act by blocking the action of COX-2, which is the enzyme responsible for the conversion of arachidonic acid to prostaglandins. Taylor P. M., Vet. Clin. North Am., 1999, 29 719-733. NSAIDs have been valuable tools in the elucidation of prostaglandin biosynthesis pathways, as well as providing a starting point for the rational design and synthesis of new anti-inflammatory drugs.
However, despite the wide use of both NSAID and opioid analgesics, current pain relievers often display large clinical (Galer et al., Pain, 1992, 49, 87-91; Portenoy et al., Pain, 1990, 43, 273-286) and experimental (Chapman et al., Pain, 1990, 43, 47-55) variability in their efficacies, side effects, and tolerance liability. This is probably because, at least in some areas, COX-2 also has a regulatory role in normal function. Thus, serious and undesirable effects such as toxicity, anemia and gastrointestinal lesions may be associated with the long-term use of NSAIDs. Opioids are generally known to cause nausea and vomiting as well as inhibition of normal propulsive gastrointestinal function in animals and man (Reisine, T., and Pasternak, G., Goodman & Gilman's The Pharmacological Basis of Therapeutics Ninth Edition 1996, 521-555) resulting in side effects such as, for example, nausea, vomiting and constipation.
Due to the drawbacks associated with currently available pain relivers, there exists a need for improved compositions and/or methods for the prevention and/or treatment of pain. The present invention is directed towards these, as well as other important ends.